Research on the genetics of domestication most often focuses on the protein-coding exons. However, exons cover only a minor part (1-2%) of the canine genome, whereas functional mutations may be located also in regions beyond the exome, in regulatory regions. Therefore, a large proportion of phenotypical differences between dogs and wolves may remain genetically unexplained. In this study, we identified variants that have high allelic frequency differences (i.e., highly differentiated variants) between wolves and dogs across the canine genome and investigated the potential functionality. We found that the enrichment of highly differentiated variants was substantially higher in promoters than in exons and that such variants were enriched also in enhancers. Several enriched pathways were identified including oxytocin signaling, carbohydrate digestion and absorption, cancer risk, and facial and body features, many of which reflect phenotypes of potential importance during domestication, including phenotypes of the domestication syndrome. The results highlight the importance of regulatory mutations during dog domestication and motivate the functional annotation of the noncoding part of the canine genome.This study seeks to further characterize the clinicopathologic spectrum of DDX41-mutated hematolymphoid malignancies.
We identified DDX41 mutations from a cohort of known or suspected hematologic disorders and reviewed the corresponding clinical, genetic, phenotypic, and morphologic findings.
DDX41 mutations were identified in 20 (1.4%) of 1,371 cases, including 8 cases of acute myeloid leukemia (AML), 5 cases of myelodysplastic syndrome (MDS), 2 cases of therapy-related MDS/AML, 1 case of primary myelofibrosis, 1 case of chronic myeloid leukemia, 1 case of clonal cytopenia of uncertain significance (CCUS), 1 case of T-cell large granular lymphocytic leukemia (T-LGL), and 1 case of multiple myeloma. DDX41-mutated neoplasms were morphologically heterogeneous with a median cellularity of 20% (range, 10%-100%). Megakaryocyte dysplasia occurred in 7 (35%) of 20 cases and trilineage dysplasia in 1 (5%). https://www.selleckchem.com/products/caspofungin-acetate.html Frequently comutated genes include a second, somatic DDX41 mutation (8/19, 42%) followed by mutations in TET2 (20%), DNMT3A (20%), ASXL1 (20%), and CUX1 (20%). Karyotypes were noncomplex in 17 (89%) of 19.
This report extends the spectrum of DDX41-mutated disorders to include CCUS, T-LGL, and plasma cell disorders. The morphologic features are heterogeneous and nonspecific, highlighting the importance of DDX41 testing during routine workup of hematolymphoid neoplasms.
This report extends the spectrum of DDX41-mutated disorders to include CCUS, T-LGL, and plasma cell disorders. The morphologic features are heterogeneous and nonspecific, highlighting the importance of DDX41 testing during routine workup of hematolymphoid neoplasms.Acute myeloid leukemia (AML) is a heterogenous malignancy characterized by distinct lineage subtypes and various genetic/epigenetic alterations. As with other neoplasms, AML cells have well-known aerobic glycolysis, but metabolic variations depending on cellular lineages also exist. Lysine-specific demethylase-1 (LSD1) has been reported to be crucial for human leukemogenesis, which is currently one of the emerging therapeutic targets. However, metabolic roles of LSD1 and lineage-dependent factors remain to be elucidated in AML cells. Here, we show that LSD1 directs a hematopoietic lineage-specific metabolic program in AML subtypes. Erythroid leukemia (EL) cells particularly showed activated glycolysis and high expression of LSD1 in both AML cell lines and clinical samples. Transcriptome, chromatin immunoprecipitation-sequencing, and metabolomic analyses revealed that LSD1 was essential not only for glycolysis but also for heme synthesis, the most characteristic metabolic pathway of erythroid origin. Notably, LSD1 stabilized the erythroid transcription factor GATA1, which directly enhanced the expression of glycolysis and heme synthesis genes. In contrast, LSD1 epigenetically downregulated the granulo-monocytic transcription factor C/EBPα. Thus, the use of LSD1 knockdown or chemical inhibitor dominated C/EBPα instead of GATA1 in EL cells, resulting in metabolic shifts and growth arrest. Furthermore, GATA1 suppressed the gene encoding C/EBPα that then acted as a repressor of GATA1 target genes. Collectively, we conclude that LSD1 shapes metabolic phenotypes in EL cells by balancing these lineage-specific transcription factors and that LSD1 inhibitors pharmacologically cause lineage-dependent metabolic remodeling.Next-generation sequencing (NGS)-based measurable residual disease (MRD) monitoring in patients with acute myeloid leukemia (AML) is widely applicable and prognostic prior to allogeneic hematopoietic cell transplantation (alloHCT). We evaluated the prognostic role of clonal hematopoiesis-associated DNMT3A, TET2, and ASXL1 (DTA) and non-DTA mutations for MRD monitoring post-alloHCT to refine MRD marker selection. Of 154 patients with AML, 138 (90%) had at least one mutation at diagnosis, which were retrospectively monitored by amplicon-based error-corrected NGS on day 90 and/or day 180 post-alloHCT. MRD was detected in 34 patients on day 90 and/or day 180 (25%). The rate of MRD positivity was similar when DTA and non-DTA mutations were considered separately (17.6% vs 19.8%). DTA mutations had no prognostic impact on cumulative incidence of relapse, relapse-free survival, or overall survival in our study and were removed from further analysis. In the remaining 131 patients with at least 1 non-DTA mutation, clinical and transplantation-associated characteristics were similarly distributed between MRD-positive and MRD-negative patients. In multivariate analysis, MRD positivity was an independent adverse predictor of cumulative incidence of relapse, relapse-free survival, and overall survival but not of nonrelapse mortality. The prognostic effect was independent of different cutoffs (above limit of detection, 0.1% and 1% variant allele frequency). MRD log-reduction between diagnosis and post-alloHCT assessment had no prognostic value. MRD status post-alloHCT had the strongest impact in patients who were MRD positive prior to alloHCT. In conclusion, non-DTA mutations are prognostic NGS-MRD markers post-alloHCT, whereas the prognostic role of DTA mutations in the posttransplant setting remains open.